Systems and methods of pH tissue monitoring

ABSTRACT

While ischemia or tissue acidosis, in cardiac tissue has been measured, systems and methods to prevent and/or reverse tissue, and in particular, cardiac acidosis were unknown. Surgeons did not know how to reverse tissue acidosis once discovered. The present invention relates to systems and/or methods of using tissue pH measurements to diagnose ischemia and to gauge the conduct of an operation, based on these pH measurements, so as to prevent and/or reverse tissue ischemia/acidosis. The current invention provides methods by which tissue acidosis can be corrected once discovered.

CROSS REFERENCES TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No.09/580,809 filed on May 26, 2000, which is a continuation-in-part ofU.S. application Ser. No. 09/339,081 filed on Jun. 23, 1999 which claimspriority to U.S. Provisional Application No. 60/136,502 filed May 28,1999, the entire teachings of the above applications being incorporatedherein by reference.

BACKGROUND OF THE INVENTION

[0002] It is well known in the art to determine the pH in body fluids byusing an electrode cell assembly and immersing the measuring electrodeinto a sample of the bodily fluid. The pH is known to be the symbol forthe negative logarithm of the H⁺ ion concentration. The pH value of theblood indicates the level of acidity of the blood. High blood acidity,which is reflected by a low pH indicates that the organs of the body arenot being provided with enough oxygen, which can ultimately proveharmful.

[0003] It is also known in the art to measure tissue pH in myocardialtissue. Measurement of pH in myocardial tissue has been used todetermine the presence of myocardial ischemia, as indicated by tissueacidosis which is reflected by a decrease in pH. During cardiac surgery,the aorta is cross clamped and the myocardium is deprived of its bloodand nutrient supply, creating the potential for damage to the heart fromischemia. Ischemia can be diagnosed by monitoring the pH of themyocardium which falls significantly and becomes acidotic duringischemia.

[0004] There is an ongoing need, however, for further improvements inmethods for diagnosing and treating ischemic tissue.

SUMMARY OF THE INVENTION

[0005] While ischemia or tissue acidosis, in cardiac tissue has beenmeasured, systems and methods to prevent and/or reverse tissue, and inparticular, cardiac acidosis were unknown. Surgeons did not know how toreverse tissue acidosis once discovered. The present invention relatesto systems and/or methods of using tissue pH measurements to diagnoseischemia and to gauge the conduct of an operation, based on these pHmeasurements, so as to prevent and/or reverse tissue ischemia/acidosis.The current invention provides methods by which tissue acidosis can becorrected once discovered.

[0006] The present invention relates to pH-guided management of tissueischemia or the use of pH measurements of tissue as a system forcontrolling diagnostic and/or surgical procedures. A preferredembodiment of the invention relates specifically to an apparatus andmethod which is applicable to patients undergoing cardiac surgery. Itemploys a tissue electrode and monitor and comprises a series of stepsthat, in a preferred embodiment, are aimed at achieving a homogeneousdistribution of cardioplegic solution during aortic clamping, and atinsuring adequate revascularization of ischemic segments of themyocardium. The method using pH-guided myocardial management guides theconduct of operations, prevents damage to the heart, extends the safeperiod of oxygen deprivation, and improves the outcome of patientsundergoing heart surgery.

[0007] The use of the pH-guided myocardial management system to identifyischemic segments of the myocardium can provide a user with options forspecific courses of conduct, both during and after, the surgicalprocedure. These options include: effecting an optimal delivery ofpreservation solutions to the heart to reduce ischemia, assessing theadequacy of coronary revascularization following a heart surgeryprocedure, identifying viable but nonfunctioning heart muscle, promptingchanges in the conduct of the surgical procedure, monitoring the pH ofthe heart muscle post-operatively and evaluating the efficacy of newermyocardial protective agents.

[0008] There are several methods of delivery of a pH electrode, used inpH-guided myocardial management, to a site of interest. The electrodecan be delivered manually by the user. The electrode can also bedelivered by a catheter through a percutaneous incision. The electrodecan also be delivered by an endoscope, a colonscope or a laparoscope toa site of interest. Thus, in a preferred embodiment of the invention,the method can be applied to other tissue measurements such as braintissue, kidney tissue, musculo-cutaneous flaps or the small or largeintestines. In another embodiment, the pH of transplanted organs, suchas liver or kidney, can be measured to assist in the diagnosis and/ortreatment of rejection since acidosis is an early sign of rejection.

[0009] Other systems and methods can also be used to measure pH,including, in certain applications, surface pH measurements, magneticresonance measurements, or optical methods using fiber optic probes orendoscopes.

[0010] When a user has found that tissue acidosis is present at a siteof interest, the user can effect an optimal delivery of preservationfluids, or cardioplegia fluids, to the heart to raise the pH of thesite. Several systems that provide optimal delivery of the cardioplegiasolutions to the site are available to the user. These include: alteringthe flow rate of the preservation fluid, altering the temperature of thefluid, altering the site of delivery, repositioning the tip of thecatheter, selectively directing the preservation fluid through themanifold, applying direct coronary artery pressure on the proximalportion of the artery, occluding the left main coronary artery with aballoon catheter, inflating the balloon of a retrograde coronary sinuscatheter, administering a bolus of cardioplegia through the orifice of aright coronary artery and accelerating a surgical procedure.

[0011] When a user has found that tissue acidosis is present at a siteof interest, the user can also prompt changes to the conduct of thesurgical procedure to raise the pH of the site. Several alternatives forchanging the surgical procedure are available to the user. Theseinclude: determining the need for revascularization of a specificsegment of the myocardium, changing the order of revascularization,providing for additional revascularization, changing the operation orthe surgeon to reduce ischemic time, canceling an operation and delayingthe weaning of a patient from cardiopulmonary bypass.

[0012] The pH electrode itself can have a cable connected to a silverwire where the silver wire is an Ag/AgCl (silver/silver chloride) wire.The cable and wires are encased in a housing which is encased in shrinktubing. The electrode has a glass stem which houses the silver wire, athermistor, a pH sensor, and a gelled electrolyte. The electrode has abendable joint which allows the user to adjust the positioning of theelectrode prior to or during use and which facilitates electrode removalafter chronic insertion. The glass stem is pointed to allow directinsertion into tissues. In a preferred embodiment, the glass stem ismade of lead glass.

[0013] The electrodes can be used in a probe that can be delivered to asite within the human body using a catheter and/or endoscope. The sensorcan be connected to a data processing system such as a personal computerthat can be used to record and process data. The computer can beprogrammed using a software module to control system operation andindicate to the user the status of the patient and changes in systemstatus and operation. The system can also prompt the surgeon as toindicated changes in a surgical procedure in progress. The computer canbe connected to a controller that operates a fluid delivery system andvarious temperature and pressure sensors can provide data for themonitoring system regarding patient status.

[0014] The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 illustrates a method of using tissue pH to identifyischemic segments of a myocardium and the options available to a user toutilize this information and take an appropriate course of action.

[0016]FIG. 2 illustrates the methods of delivery of a pH electrode tocardiac tissue.

[0017]FIG. 3 illustrates a method of effecting an optimal delivery ofpreservation solution to the heart during surgery.

[0018]FIG. 4 illustrates a method of using the pH electrode to measurethe condition of tissue and alter the conduct of an operation involvingthe tissue.

[0019]FIG. 5 illustrates a sectional view of an embodiment of a pHelectrode.

[0020]FIG. 6 illustrates a turkey foot cardioplegia delivery system andtools.

[0021]FIG. 7A shows a manifold cardioplegia delivery system and toolsattached to a heart.

[0022]FIG. 7B shows a cannula placed within the left main coronaryartery of the heart.

[0023]FIG. 8 shows a coronary sinus cannula connected to a venouscannula.

DETAILED DESCRIPTION OF THE INVENTION

[0024]FIG. 1 illustrates a method of using tissue pH to identifyischemic segments of the heart, which are regions of the heart musclethat are not receiving an adequate blood and nutrient supply, and theoptions available to a user to take advantage of this information andpursue an appropriate course of action. A user would first deliver a pHelectrode to a patient's heart 10. The user would then measure thetissue pH as displayed on a monitor 12 and determine whether or notthere was acidosis present in the tissue 14. If there is no tissueacidosis 16, the pH would be again measured 12. In a preferredembodiment, the pH is continually measured by the electrode with the pHmeasurements displayed on a monitor. If acidosis existed in the tissue18, however, the user could use this information to take appropriateaction such as, but not limited to, the following:

[0025] A user can effect an optimal delivery of the preservationsolutions to the heart through one or more of a compendium of specificinterventions 20. To perform open heart surgery, the aorta has to beclamped thus depriving the heart muscle from its blood, nutrient, andoxygen supply. A preservation solution, often referred to as acardioplegic solution, is normally perfused into the heart and its bloodvessels to prevent time-dependent ischemic damage. It has been shownthat the measurement of tissue pH, which reflects, in part, the washoutof the hydrogen ion generated by the metabolic processes, is a goodindicator of the regional distribution of the preservation solution. Ithas also been shown this distribution to be markedly heterogenous andunpredictable, with segments of the myocardial wall suffering fromacidosis because of failure of the cardioplegic solution to reach thesesegments. The main objective of pH-guided myocardial management is toprevent tissue acidosis in all the segments of the myocardium throughoutthe course of open heart surgery. This is achieved by insuring anadequate and a homogeneous delivery of the cardioplegic solution and anadequate revascularization of ischemic segments of the heart. These areachieved by maintenance of the myocardial pH as near normal as possible,with normal pH ranging between 7.2 and 7.4.

[0026] A user can also assess the adequacy of coronary revascularizationfollowing coronary artery bypass grafting, balloon dilatation orintracoronary stenting 22. This functionality employs the rate ofwashout of the hydrogen ion accumulating in the tissues during ischemiaas an indication of the magnitude of tissue blood flow. Followingrestoration of flow through a newly constructed aorto-coronary bypassgraft, no change in the pH of a myocardial segment subtended by thatgraft indicates inadequate revascularization. On the other hand, a risein the pH of more than 0.1 pH units indicates restoration of effectivetissue flow to the ischemic myocardium.

[0027] A user can also identify viable but non-functioning heart muscle24, known as hibernating myocardium, which improves its function withadequate coronary revascularization. pH-guided myocardial management hasdemonstrated that the ability of the non-contractile myocardial wallsegment to produce acid, i.e. to exhibit tissue acidosis, is anindication of the viability and reversibility of dysfunction in thissegment. Hence the procedure provides a tool with which the viability ofthe non-contractile myocardial segment can be assessed.

[0028] A user can also prompt specific changes in the conduct of theoperation 26 after obtaining information regarding tissue pH. Thesechanges in operating procedure are outlined in greater detail in FIG. 4.

[0029] A user can also monitor the acid-base status of the heart musclein the post-operative period 28 and identify impending problems. Thisfunctionality allows the depiction of ischemic events in the intensivecare unit within the first 72 hours postoperatively. This methodology iscapable of continuous monitoring of regional tissue metabolism and acidbase balance in a patient, post-surgery. A fall in the myocardial pH ofmore than 0.1 pH units in the face of a stable blood pH is indicative ofmyocardial ischemia. The more severe the fall in the pH the more themagnitude of the ischemic damage. This functionality is achieved byimplanting the electrodes in the myocardium at the time of the operationand exteriorizing them through a special chest tube. The electrodes arepulled out in the surgical intensive care unit (SICU) after themonitoring is terminated by simply pulling on them along with the chesttube which houses them.

[0030] The user can also evaluate the efficacy of newer myocardialprotective agents and methods in the prevention of tissue acidosis andthe improvement of patient outcomes 30. To improve myocardialprotection, a number of agents are being proposed as additions to thecardioplegic solution, and new modalities for the administration ofcardioplegia are being sought. pH-guided myocardial management providesa metabolic marker which can enable the assessment of the efficacy ofthese new agents and modalities in improving the degree ofintraoperative protection, the hallmark of which can be the degree ofprevention of acidosis during the period of aortic clamping. Thevariable employed to compare these methods of myocardial protection isthe integrated mean myocardial pH during the period of aortic clamping.The higher the integrated mean pH during this period, the better is thedegree of myocardial protection.

[0031]FIG. 2 illustrates various methods of delivery of a pH electrodeto cardiac tissue. A user can implant the pH electrode using directinsertion 40. This can include opening the chest cavity of a patientduring a cardiac surgery procedure and placing the electrode into thepatient's cardiac tissue by hand. The user can also insert the pHelectrode by means of a catheter using a percutaneous incision 42. Auser can also insert the pH electrode by using an endoscope, colonscopeor laparoscope 44. The user can then measure the pH of the tissue 46 anddetermine whether there is acidosis in the tissue 48. If no acidosis isfound 50, the pH of the tissue can again be measured 46. If acidosis isfound in the tissue 52, the user can then take an appropriate course ofaction 54, as outlined in FIG. 1.

[0032]FIG. 3 illustrates a method of providing for an optimal deliveryof preservation solution to a heart during surgery. In this method, auser can first measure cardiac tissue pH 60 and determine whether thereis acidosis in the tissue 62. If no acidosis is found 64, the pH of thetissue can again be measured 62. In a preferred embodiment, the pH iscontinuously measured and monitored. If acidosis is found in the tissue66, the user can then effect an optimal delivery of the preservationsolutions to the heart through one or more of a compendium of specificinterventions. Interventions to be used to effect an adequate and ahomogeneous delivery of the cardioplegic solution include, but are notlimited, to the following maneuvers:

[0033] The user can alter the flow rate of the preservation solution 68to provide an optimal delivery of the cardioplegia solution. Theperfusionist controls the flow rate of the cardioplegic solutionadministered. pH-guided myocardial management has demonstrated thatpatients and myocardial segments differ in the flow rate necessary toprevent acidosis. Therefore, changing the flow rate of the cardioplegiasolution can alter and improve tissue pH.

[0034] The user can also alter the temperature of the preservationsolution 70 to optimize solution delivery. Changes in myocardialtemperature, which can range widely in the course of cardiac surgery,effect various degrees of vasoconstriction and vasodilatation of thecoronary vasculature. This, in turn, will effect the distribution of thecardioplegic solution and also the level of tissue acidosis. Avoidanceof tissue acidosis can be achieved either by cooling or by re-warmingthe cardioplegic solution, depending on the effect of temperature on theregional distribution of the cardioplegic solution. pH-guided myocardialmanagement has demonstrated that the effect of temperature on theregional distribution of the cardioplegic solution is totallyunpredictable and, hence, continuous monitoring of myocardial tissue pHallows the determination of the myocardial temperature which is mostlikely to prevent myocardial acidosis. Opposite effects on myocardial pHhave been observed from patient to patient with both cooling andrewarming. In general, however, giving warm cardioplegia effected animprovement in tissue pH in most patients.

[0035] To provide an optimal delivery of the solution, the user can alsoalter the site of delivery of the cardioplegic solution 72. Thecardioplegic solution can be delivered through several sites: antegradethrough the aortic root, antegrade through the orifice of the rightand/or left main coronary arteries, antegrade through the proximal endsof newly constructed grafts, and retrograde through the coronary sinus.pH-guided myocardial management allows the surgeon to choose the site orcombination of sites of administration which can best avoid regionalacidosis.

[0036] The user can reposition the tip of the catheter through which thecardioplegic solution is delivered 74 to optimize delivery. This mayneed to be performed in patients with a very short left main coronaryartery when cardioplegia is administered through the orifice of the leftmain. It can also be useful in pulling back on a retrograde catheterwhich is pushed too far into the coronary sinus.

[0037] The user can also selectively direct the cardioplegic solutionthrough a manifold so as to reduce the steal of the solution 76. Thecardioplegic solution can be delivered through a manifold having severalcatheters radiating from a single source. This arrangement of themanifold is known as a “turkey foot.” When the cardioplegic solution isadministered through more than one of these catheters simultaneously,there is a marked heterogeneity in the distribution of the solution tothe various myocardial segments supplied by these catheters. Thesolution often moves preferentially into the catheter supplying themyocardial segment with least resistance, usually the myocardial segmentwith least coronary artery disease. This is what is referred to as a“steal phenomenon.” Monitoring myocardial pH, which capitalizes on thefact that the rate of washout of the hydrogen ion in tissue isindicative of the magnitude of tissue flow, can determine which segmentsof the myocardium are receiving the cardioplegic solution and whichsegments are deprived of cardioplegia because of the “steal” phenomenon.When steal is encountered, homogeneity of the distribution of thecardioplegic solution can be achieved by occluding the cathetersresponsible for the steal and by specifically directing the flow onlyinto the areas exhibiting acidosis.

[0038] The user can also apply direct coronary artery pressure on theproximal portion of the artery to distally direct cardioplegia flowthrough a newly constructed graft 78. This pressure can force thecardioplegia solution to an area with low pH, to lower tissue acidosisin that area.

[0039] The user can perform a balloon catheter occlusion of the orificeof the left main coronary artery during the delivery of retrogradecardioplegia through the coronary sinus or through the proximal ends ofrecently constructed saphenous vein grafts 80. The balloon catheterocclusion of the left main coronary artery prevents the stealphenomenon, where the solution follows the path of least resistance, andforces the cardioplegia solution to an area of low pH. This process canreverse acidosis of an area showing a low pH.

[0040] The user can also inflate the balloon of a retrograde coronarysinus catheter while the cardioplegic solution is being administeredantegrade 82. Normally, if cardioplegia is being delivered antegrade andretrograde simultaneously, the balloon in the coronary sinus is keptdeflated. A more homogeneous distribution of the cardioplegic solutioncan be achieved if the balloon in the coronary sinus is kept inflatedwhile the cardioplegia is delivered simultaneously antegrade andretrograde.

[0041] The user can also administer a bolus of cardioplegia through theorifice of the right coronary artery when the latter is a dominant,non-obstructed vessel 84. In the course of an open heart operation inwhich the aortic root is open, cardioplegia can be administered throughthe orifice of the right coronary artery in addition to the orifice ofthe left coronary artery. This, however, can be tedious and timeconsuming, hence it is not a common practice. pH-guided myocardialmanagement has shown that the posterior left ventricular wall is morevulnerable to refractory myocardial acidosis if the right coronaryartery is dominant and no cardioplegia is administered through it.Hence, if in the course of pH-guided myocardial management, refractoryacidosis is encountered in the posterior wall, administering a bolus ofcardioplegia through the orifice of the right coronary artery, if thelatter is dominant, can insure adequate delivery of the cardioplegicsolution to the posterior wall and can reverse the acidosis.

[0042] A user can also accelerate the surgical procedure 86 when tissueacidosis is present. By monitoring tissue acidosis, a user can avoideither using his time wastefully or attempting nonstandard orpotentially ineffectual surgical procedures. Also, in a few patients,less than 5%, there is no known method to prevent tissue acidosis andthe surgical procedure must be accelerated. With the acceleration of aprocedure, the aorta, which is clamped during the surgery, is unclampedsooner than planned, thus allowing oxygen rich blood to reach the heartmuscle, thereby reversing acidosis.

[0043] In the event that one of the described options, 68 through 86,fails to relieve the ischemic condition, as evidenced by the display oftissue pH levels on the pH monitor, the user can use any of the otherdescribed options to attempt to raise tissue pH.

[0044]FIG. 4 illustrates a method of using the pH electrode to promptspecific changes in the conduct of an operation after determining thereis tissue acidosis. In this method, a user first measures cardiac tissuepH 90 and determines whether there is acidosis in the tissue 92. If noacidosis is found 94, the pH of the tissue can again be continuously orperiodically measured 90. If acidosis is found in the tissue 96, theuser can then change the conduct of the procedure 98.

[0045] These changes can include, but are not limited, to the followingmaneuvers. First, the determination of the need for therevascularization of a specific segment of myocardium 100. The abilityto identify which specifically are the segments of the myocardium thatneed revascularization can be lifesaving. Segments requiringrevascularization can be determined by either examining the onset ofregional acidosis in the course of an operation or the response of themyocardial pH to atrial pacing. The response to atrial pacing can beutilized intra-operatively, postoperatively in the SICU, and in thecardiac catheterization laboratory.

[0046] The user can also change the order of revascularization.pH-guided myocardial management allows the surgeon to revascularize themost ischemic segments of the myocardium first so as to minimize thedegree of acidosis encountered in the course of aortic clamping.

[0047] The user can also change the procedure by providing additionalrevascularization of the heart 104. pH-guided myocardial managementinvolves identifying ischemic segments of the left ventricular wall thatrequire revascularization, often unplanned preoperatively.

[0048] The user can also change the operation or the surgeon to reducethe duration of the ischemic time 106. pH-guided myocardial managementallows for reductions in the magnitude of the planned operation inseveral ways. When pH monitoring depicts a significant amount ofmyocardial acidosis which cannot be corrected, the need to reduce theischemic time becomes more important than the potential benefits ofcertain parts of the operation that can be dispensed with, such as theconstruction of an additional graft. pH monitoring also allows thesurgeon to abandon a planned part of the operation because it uncoversno real need for this part. In this context, pH-guided myocardialmanagement also plays a major value in the teaching of residents becauseit provides the attending surgeon with the information on what parts ofthe operation he/she can give to the resident, and what part theattending surgeon can be doing himself/herself, since residents,particularly early in their training, can be fairly tardy in performingthese operations.

[0049] The user can also cancel an operation 108 if, based on the pHmeasurements, the risk of the procedure is found to exceed the benefit.

[0050] Lastly, the user can delay the weaning from cardiopulmonarybypass until the oxygen debt, represented by residual acidosis duringreperfusion, is fully paid 110.

[0051] Weaning from cardiopulmonary bypass in the presence of myocardialacidosis may cause the hemodynamics to deteriorate postoperatively,often prompting the re-institution of cardiopulmonary bypass. When theheart is subjected to significant ischemia during the period of aorticclamping or reperfusion, a significant amount of time may be neededuntil the ischemia reverses to normal levels.

[0052] In the event that one of the described options, 100 through 106,fails to relieve the ischemic condition, as evidenced by the display oftissue pH levels on the pH monitor, the user can use any of these otherdescribed options to attempt to raise tissue pH.

[0053]FIG. 5 illustrates an embodiment of a pH electrode 136 used tomonitor tissue acidosis. The electrode 136 can have a cable 112connected to a silver wire 114. In a preferred embodiment, the silverwire 114 is an Ag/AgCl (silver/silver chloride) wire. In anotherpreferred embodiment, the cable 112 is connected to the silver wire 114by a platinum wire 116 passing through a glass seal 118. The cable 112and wires 114, 116 are encased in a housing 120 which is encased inshrink tubing 122. The electrode 136 has a glass stem 124 which housesthe silver wire 114, a thermistor 126, a pH sensor 128, and a gelledelectrolyte 130. The electrode 136 can also have a suture groove 132 toallow the electrode 136 to be secured to the site where it is used. Theelectrode 136 can also have a bendable joint 134 which allows the userto adjust the positioning of the electrode 136 prior to or during use.The glass stem 124 is pointed to allow direct insertion into tissues. Ina preferred embodiment, the glass stem 124 is made of lead glass. Theelectrode can be sterilized by ethylene oxide or gamma irradiation. A pHelectrode suitable for use with the invention is available from VascularTechnology Inc., 175 Cabot Street, Lowell, Mass. This particularelectrode can be inserted into tissue to a depth of up to 10 mm, has adiameter of 1 mm, and employs a pH sensor in the distal 4 mm of theprobe.

[0054] Tissue pH is an important clinical measurement. Local acidosis,which can be measured as a distinct drop in pH, has been associated withischemia. Temperature is preferably measured simultaneously with the pHto allow for the calibration and temperature correction of the tissue pHmeasurement. Temperature correction of the pH is important, particularlyin procedures, such as open-heart surgery, which require significantcooling. The pH electrode uses combination pH/temperature sensors, eachof which contains a temperature-sensing element mounted inside thepH-sensing sensor.

[0055] Glass pH electrodes are the method most commonly used to obtainaccurate clinical pH measurements. They consist of a hollow glass sensorfilled with electrolyte that is in turn in contact with an internalreference wire. Due to the nature of the glass used, an electricpotential is developed across the glass. This potential is proportionalto the difference between the pH of the analyte solution in contact withthe exterior surface of the glass and the essentially constant pH of theinternal buffer solution.

[0056] In order to make an electrical measurement, a complete electriccircuit must be formed. Therefore, a second electrical contact with theanalyte solution must be made. This is accomplished through the use of aneedle reference electrode. It consists of a silver chloride needle incontact with a constant molarity salt solution. The salt solution isplaced in contact with the analyte solution, i.e., the patient's tissue,using a suitable isolation mechanism, in this case through the use ofgelled salt solution that has been placed in a flexible tube, the openend of which is placed in contact with the patient.

[0057] The Nernst equation predicts that under constant environmentalconditions, the output of the glass pH electrode is linear with pH.Therefore, the electrical output of the sensor can be converted to pH bythe use of a simple straight-line curve-fit. This will requiredetermining the electrical output of the electrode at two different pHvalues, from which the slope and offset constants for the straight-lineequation can be calculated. The commonly available standards buffers forpH electrode calibration have pH values of 4, 7, and 10. The 4 and 7buffers have been chosen for use with this system. The 7 pH buffer waschosen because the electrode's zero-potential point is near pH 7. The0.4 buffer was chosen because pH values of the greatest interest liesomewhat below pH 7.

[0058] The theoretical sensitivity-the slope-of this type of electrodeis 59.16 mV/pH at 25° C. For real electrodes, it tends to be a littleless, the value being slightly different from one electrode to anotherand, for a given electrode, varying over its useful life.

[0059] The zero potential point is defined, as that analyte pH value forwhich the measured output voltage is zero, after correcting for anydifference in the salt concentrations of the internal and referencesolutions. The zero potential point should occur, therefore, when theanalyte pH value is the same as the pH value of the pH sensor's internalbuffer. If a measurement is actually made under these conditions,however, a non-zero potential will, in general, be measured. This occurswhen the CI connection that the sensor's internal reference wire isexposed to differs from the concentration that the reference needle isexposed to, or if both reference wires are not made of the samematerial. In this system, the reference needle is immersed in asaturated KCl gel, while the sensor's internal reference wire is exposedto an 0.87 M concentration of KCl in the internal buffer. Thisdifference results in a measured potential of about +30 mV at 25° C.when the analyte has the same pH value as that of the internal buffers,nominally 6.33 pH at 25° C. Thus, in order to measure the true zeropotential point, it is necessary to correct the measured voltage bysubtracting 30 mV from it. The pH 7 buffer is used during calibrationfor zero point calibration is the closest readily available buffer valueto 6.33.

[0060] Since there is some variation in output from the ideal values asjust described, both from sensor to sensor and over extended periods oftime for the same sensor, the pH sensors must be calibrated prior toeach use. This is accomplished automatically during the calibrationprocedure by placing the sensors first in the slope buffer (4.00 pH) andthen in the zero potential point buffer (7.00 pH). The microprocessorreads the output of the sensors in mV, correcting for the saltdifferential, determines when the readings are stable and then computesthe slope and offset calibration factors for each sensor. Both the slopeand zero potential point vary with temperature and are corrected for bythe monitor's software.

[0061] The pH electrode's combination pH/temperature sensor uses aprecision thermistor element to measure temperature. The thermistor isone of the most common temperature measuring devices in use. It consistsof a small bead of metallic oxide semiconducting ceramic. The material'selectrical resistance varies inversely with temperature in a non-linearmanner.

[0062] To measure temperature, the thermistor is electrically placed inseries with a fixed resistor in the monitor that has precisely knownresistance. A voltage is applied across the series combination and thevoltage at the junction of the thermistor and resistor is measured. Thismeasured value, in conjunction with the known values of the fixedresistor and of the applied voltage, is used to calculate the resistanceof the thermistor. The temperature is then determined by means of alook-up table stored in the microprocessor program. The thermistorsensors used with this system are manufactured to a level of precisionthat makes individual calibration by the user of the system unnecessary.

[0063] The pH electrode can be pre-calibrated and packaged such that thetip of the electrode is sealed within a sleeve or a sleeve pocketcontaining a pH 4.0 buffer. The sleeve pocket can be formed of a plasticmaterial and can have a 3 mm internal diameter. Prior to its insertionin the patient, the sleeve pocket can be removed, the electrode tipwiped dry with a gauze, and the electrode inserted into a beakercontaining a pH 7.0 buffer. The calibration is completed at this point.Packaging the electrode within a pH 4.0 buffer allows the electrode toremain moist through its storage, a factor which is necessary for propercalibration, and reduces the steps required for electrode calibration toa single step. The software in the electrode monitor can be modified toreflect the single step calibration.

[0064] The monitor, to which the pH electrode, the reference electrode,and thermistor are attached, processes the signals and continuallyrecords and displays the following data at 20 second intervals orless: 1) the tissue pH in pH units, 2) the tissue hydrogen ionconcentration [H⁺] in nmoles, 3) the tissue temperature in ° C., 4) thepH corrected for 37° C., and 5) the tissue hydrogen ion concentration[H⁺] is calculated as the inverse log of pH. The correction for 37° C.is based on a factor of 0.017 pH units/° C. which was derived based onexperiments performed in the inventor's laboratory. In addition, themonitor allows for the calculation of integrated mean pH, [H⁺], andtemperature over a specific period of time by signaling at the beginningand at the end of the specified period. A slave monitor is attached tothe unit and placed in front of the surgeon providing a customizedcontinuous display of the data. The continuous real-time display of thedata allows for prompt institution of pH-guided myocardial management toprevent or reverse myocardial tissue acidosis.

[0065] Several devices or tools can be used in pH guided myocardialmanagement during cardiac surgery and in the assessment of myocardialviability. The maintenance and distribution of cardioplegic solution tospecific myocardial segments during cardiac surgery can be achievedusing several different devices and approaches.

[0066]FIG. 6 illustrates a “turkey foot” cardioplegia delivery system140 (Medtronic, Grand Rapids, Mich.). The delivery system 140 inconjunction with the electrode can form a myocardial management system.The system 140 can also include a data processing system 160, such as acomputer, and a controller 158. The data processing system 160 can beprogrammed to receive measured data 162, such as the status of thepatient and changes in system status. The data processing system 160 canbe attached to a fluid source of fluid delivery system 144. The dataprocessing system 160 can also be attached to the fluid source throughthe controller 158. The controller 158 can operate the fluid deliverysystem. The controller 158 can control the flow rate of a preservationfluid or cardioplegia fluid delivered to a surgical site. The controller158 can also control the temperature of a preservation solution and adelivery site of a preservation solution. The system 140 has a pluralityof controls 142 which can be used to adjust and selectively administerthe amount of cardioplegia solution delivered from a source 144 tovarious cardiac attachment sites. The system 140 can include an occluderor valve 146 which controls the flow of the cardioplegic solution. Thesystem 140 includes several delivery devices attached between thecardioplegia source 144 and various cardiac sites. These devices allowthe delivery of cardioplegic solution to their respective cardiac sites.One device is a cannula 148 (Sarns Inc., Ann Arbor, Mich.) which can beinserted in the aortic root. Another device is a Spencer cannula 150(Research Medical, Inc., Midvale, Utah) which can be inserted within theorifice 156 of the left main coronary artery. This insertion into theorifice 156 is shown in FIGS. 7A and 7B. Another device is a malleablemetallic catheter 152 (Medtronic, Grand Rapids, Mich.) which can beinserted within the orifice of the right main coronary artery. Thecatheter 152 is also shown in FIG. 7A in an uninserted state. Anotherdevice is a 14 gauge beaded needle (Randall Faichney Corp., Avon, Mass.)which can be attached to the proximal end of a saphenous vein graft forthe delivery of cardioplegia. The attachment to the vein graft is alsoshown in FIG. 7A.

[0067] Blocking the orifice of the left main coronary ostium with aspherical catheter such as a Spencer cannula 150 (Research Medical,Inc., Midvale Utah) or balloon tipped catheter such as a #3F FogertyCatheter (Ideas For Medicine, St. Petersburg, Fla.), while providingcardioplegia through other sites of 140, can also be used toredistribute cardioplegia solution during cardiac surgery. Also,applying temporary occlusive pressure to a coronary artery proximal tothe site of insertion of a new vein graft while perfusing a cardioplegicsolution through the proximal end of the graft can also be used tore-direct cardioplegic fluid during cardiac surgery. Occlusive pressurecan be maintained with a gauze “peanut” at the tip of a Kelly clamp(Allegiance Healthcare Corp., McGaw Park, Ill.).

[0068] A Guntrie balloon tipped cannula (Medtronic, Grand Rapids, Mich.)can also be attached to the system 140 and inserted in the coronarysinus for selective administration of cardioplegia in a retrogrademanner. The cannula 170 is illustrated in FIG. 8. In this figure, it isillustrated attached through tubing 176 to the venous cannual 178. Thisallows manipulating the pressure in the coronary sinus to improvecardioplegia delivery to the tissues as part of pH-guided myocardialmanagement. The pressure can be manipulated by inflating a coronarysinus balloon 172 with the fluid orifice of the coronary sinus catheterclosed, and delivering the cardioplegia antegrade. The 1 mm tubing 176connecting 170 to 178 creates back pressure which will improve deliverywithout interfering with adequate antegrade cardioplegia flows. Theopening or closing of the fluid orifice of the coronary sinus catheter170 can be controlled by a valve 184. The venous cannula 178 is normallyinserted in the course of cardiopulmonary bypass with its tip 182 in theinferior vena cava and its more proximal orifice 180 in the rightatrium.

[0069] Changing the tissue temperature by manipulating the temperatureof the cardioplegic solution using a water heater/cooler, such as thatmanufactured by Sarns, Ann Arbor, Mich., can aid in managing myocardialpH during cardiac surgery. Also, changing the perfusion pressure of thecardioplegic solution by changing the rate of cardioplegia flow using acardioplegia system such as an HE30 Gold cardioplegia system (BaxterCorporation, Irvine, Calif.) can aid in managing myocardial pH duringcardiac surgery.

[0070] Tools can also be used for the assessment of myocardial viabilityand the determination of the physiologic significance of coronarystenosis. The tools can be used in either an operating room or a cardiaccatheterization lab.

[0071] In the operating room, pacing wires (Ethicon, Somerville, N.J.)can be placed over the right atrium and connected to an externalpacemaker (Medtronic, Grand Rapids, Mich.). A pH electrode can also beinserted into the myocardium. A fall in myocardial pH in response to 5minutes of rapid atrial pacing can indicate tissue ischemia and also canindicate that the myocardial segment in which the electrode is placed isviable.

[0072] In the cardiac catheterization laboratory, the pH electrode canbe mounted at the tip of a long 0.014 gauge wire and inserted through aregular 6 french cardiac catheterization catheter such as thatmanufactured by Cordis (Miami, Fla.). The catheter tip can be positionedperpendicularly against the ventricular wall of the segment subtended bythe coronary artery being investigated and the pH electrode pushed topenetrate into the subendocardium. Preferably, the electrode is pushedto penetrate 5 mm into the subendocardium. Pacing is achieved via apacing wire advanced into the right ventricle (Medtronic, Grand Rapids,Mich.) and attached to an external pacemaker (Medtronic, Grand Rapids,Mich.). Again, a fall in myocardial pH in response to 5 minutes of rapidarterial pacing can indicate tissue ischemia.

[0073] While the pH electrodes and monitoring system have been describedfor use in determining the ischemia of cardiac tissue, the pH system andmethods can be used in other types tissue as well. The pH system can beused to monitor rejection in organ transplantation, to assess mesentericischemia, to monitor and assess brain blood flow and to monitor flaps inplastic surgery.

[0074] The pH electrode can be used to monitor the kidney in the courseof and following kidney transplantation. The pH electrode can be used inthe monitoring of tissue perfusion to the kidney in the course of majorsurgery and, in particular, during kidney transplantation. The electrodeis readily implantable in the kidney in a manner similar to the heart,and a tissue pH level of 7.2 and above indicates adequate tissueperfusion. Damage to the kidney, particularly during excision of thekidney for the purpose of donor related cardiac transplantation, can bedetected and avoided, thus insuring a better outcome of the donorrelated kidney transplantation. Preservation of the kidney duringtransport prior to transplantation can also be insured by monitoring andmaintaining the pH at normal levels. This can be achieved with constantperfusion of the kidney with blood in a specially designed apparatus fororgan perfusion.

[0075] Following kidney transplantation, keeping the electrode in thekidney throughout the immediate 48 hours post-operatively can allow formonitoring initial ischemia and can allow for reversing of this ischemiawith operative interventions. Ischemia during this period can herald asignificantly bad outcome. Assessment of the transplanted kidney,function and detection of its rejection can also be performed by placingthe electrode on a catheter and passing it retrograde into the calyx ofthe kidney. Puncturing the calyx of the kidney along with the kidneyparenchyma, similar to what was described above for the heart, canindicate impending or actual rejection and, as such, would be indicativeof adverse outcome. Early detection of acidosis can prompt majortreatment of rejection, and thus can improve the outcome of kidneytransplantation.

[0076] Each electrode can be used also for the assessment of theadequacy of the revascularization of the kidney in the course of renalartery revascularization. The efficacy of the revascularization of acritically stenod renal artery can be determined intra-operatively in amanner similar to the efficacy of the revascularization of the coronaryarteries. Failure to reverse acidosis with revascularization shouldprompt additional intra-operative measures to reverse the acidosis, andhence, avoid adverse outcome of revascularization. As in the heart,failure to reverse the acidosis with revascularization is indicative ofthe inadequacy of the revascularization process and provides a guide foradditional intra-operative management to improve the situation andimprove the outcome of the revascularization.

[0077] The pH electrode can also be used to monitor the liver during andfollowing liver transplantation. The pH electrode can be inserted intothe liver to provide important data similar to that of the kidney,described above. The description of the use of the electrode in thekidney is applicable to the liver in terms of the use of the pHelectrode in monitoring the intra-operative course, identifying earlyrejection, and instituting measures to reverse the rejection process.

[0078] The electrode can also be used in monitoring the periphery incritical care. Insertion of the electrode in the subcutaneous tissue ofthe periphery should provide information on the adequacy of tissueperfusion. Acidosis measured at these sites, primarily in thesubcutaneous tissue of the distal half of the lower extremity, canindicate an inadequate cardiac output, and can prompt the institution ofmeasures to improve cardiac output or tissue perfusion. These measurescan include pharmacologic manipulations and/or insertion of anintra-aortic balloon (Arrow International, Reading, Pa.) in thedescending aorta, for example. Currently, only measures of centralhemodynamics are used to assess and treat low cardiac output syndrome.Measuring the pH in the periphery provides a more superior alternativebecause it provides a true measure of tissue perfusion which is theultimate goal in the maintenance of an “adequate” cardiac output.

[0079] The electrode can also be used within the muscle and subcutaneoustissue of flaps in plastic surgery. It has been demonstrated that tissueacidosis with the pH electrode indicates compromised viability of skinand subcutaneous flaps. The electrode is placed post-operatively withinthe edge of the flap and the pH is monitored up to three or four dayspost-operatively. A fall in pH prompts an intra-operative interventionand a revision of the flap to prevent its subsequent failure.

[0080] The pH electrode can also be used in the colon in the assessmentand treatment of intestinal ischemia. To assess and reverse intestinalischemia, the pH electrode can be placed on a wire in a manner similarto that described for the heart during cardiac catheterization above.This pH electrode-tipped wire can be inserted through a colonscope, suchas that manufactured by Olympus Medical, Seattle, Wash., during regularcolonoscopy into the distal ileum. Intra-luminal pH in the ilium is areliable measure of the adequacy of the perfusion. Intra-luminalacidosis in the ilium indicates intestinal ischemia, and can promptmaneuvers to either reverse the ischemia or to prevent its adverseoutcome. Knowledge of intra-luminal pH in the ilium allows theinitiation of operative interventions, such as exploration of theabdomen with the possible resection of intestine, for example, as wellas pharmacologic interventions to improve cardiac output and tissueperfusion.

[0081] The pH electrode can be used in other organs. In addition to theorgans mentioned above, tissue acidosis can be measured, manipulated,and reversed by inserting the pH electrode, attached to the pHmonitoring system, in organs such as the brain, the bladder, thediaphragm, and the small intestine.

[0082] Acidosis can prematurely trigger and accelerate cell apoptosis,or programmed cell death. In the heart, apoptosis may manifest in lateadverse outcomes, mainly progressive heart failure. During the course ofopen heart surgery, moderate to severe acidosis is encountered, at leastin one segment of the left ventricle, in more than 50% of the patients.The prevention of the onset of myocardial tissue acidosis by pH-guidedmyocardial management in the course of open heart surgery reduces oreliminates the potential of triggering apoptosis, and hence reduce oreliminate the potential of late adverse postoperative outcomes.

[0083] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

[0084] The claims should not be read as limited to the described orderor elements unless stated to that effect. Therefore, all embodimentsthat come within the scope and spirit of the following claims andequivalents thereto are claimed as the invention.

What is claimed:
 1. A method of effecting a change in a surgicalprocedure comprising the steps of: contacting tissue of a patient with apH electrode; measuring the pH of the tissue with the pH electrode tomonitor the pH of the tissue during the surgical procedure; determiningif the tissue pH falls below a threshold level indicative of acidosis;and determining the need for revascularization of the tissue if thetissue pH measurement falls below the threshold level indicative ofacidosis.
 2. The method of effecting a change in the surgical procedureof claim 1 wherein the step of contacting tissue further comprisesinserting the pH electrode into the tissue.
 3. The method of effecting achange in the surgical procedure of claim 1 wherein the step ofdetermining the need for revascularization further comprises identifyingspecific segments of the tissue requiring revascularization by at leastone of examining the onset of acidosis during the procedure and theresponse of the tissue pH to atrial pacing.
 4. The method of effecting achange in the surgical procedure of claim 3 wherein the response toatrial pacing can be used during at least one of an intra-operativeduration and post-operative duration.
 5. The method of effecting achange in the surgical procedure of claim 1 wherein the step ofcontacting the pH electrode to the tissue of a patient is performedmanually.
 6. The method of effecting a change in the surgical procedureof claim 1 wherein the step of contacting the pH electrode to the tissueof a patient is performed by a percutaneous catheter.
 7. The method ofeffecting a change in the surgical procedure of claim 1 wherein the stepof contacting the pH electrode to the tissue of a patient is performedusing one of a laparoscope, an endoscope and a colonscope.
 8. The methodof effecting a change in the surgical procedure of claim 1 wherein thetissue is myocardial tissue.
 9. A method of effecting a change in asurgical procedure comprising the steps of: contacting tissue of apatient with a pH electrode; measuring the pH of the tissue with the pHelectrode to monitor the pH of the tissue during the surgical procedure;determining if the tissue pH falls below a threshold level indicative ofacidosis; and changing the order of revascularization of the tissue ifthe tissue pH measurement falls below the threshold level indicative ofacidosis.
 10. The method of effecting a change in the surgical procedureof claim 9 wherein the step of contacting tissue further comprisesinserting the pH electrode into the tissue.
 11. The method of effectinga change in the surgical procedure of claim 9 wherein the step ofchanging the order of revascularization further comprises firstrevascularizing most ischemic segments of the tissue.
 12. The method ofeffecting a change in the surgical procedure of claim 9 wherein the stepof changing the order of revascularization further comprisesrevascularizing most ischemic segments of myocardium tissue to minimizethe degree of acidosis during aortic clamping.
 13. The method ofeffecting a change in the surgical procedure of claim 9 wherein the stepof contacting the pH electrode to the tissue of a patient is performedmanually.
 14. The method of effecting a change in the surgical procedureof claim 9 wherein the step of contacting the pH electrode to the tissueof a patient is performed by a percutaneous catheter.
 15. The method ofeffecting a change in the surgical procedure of claim 9 wherein the stepof contacting the pH electrode to the tissue of a patient is performedusing one of a laparoscope, an endoscope and a colonscope.
 16. Themethod of effecting a change in the surgical procedure of claim 9wherein the tissue is myocardial tissue.
 17. A method of determining achange in a surgical procedure comprising the steps of: contactingtissue of a patient with a pH electrode; measuring the pH of the tissuewith the pH electrode to monitor the pH of the tissue during thesurgical procedure; determining if the tissue pH falls below a thresholdlevel indicative of acidosis; and reducing a duration of ischemic timeof the tissue if the tissue pH measurement falls below the thresholdlevel indicative of acidosis.
 18. The method of effecting a change inthe surgical procedure of claim 17 wherein the step of contacting tissuefurther comprises inserting the pH electrode into the tissue.
 19. Themethod of effecting a change in the surgical procedure of claim 17wherein the step of reducing the duration of ischemic time furthercomprises altering the procedure such as by one of shortening theprocedure, changing the surgeon, and canceling the procedure.
 20. Themethod of effecting a change in the surgical procedure of claim 17wherein the step of contacting the pH electrode to the tissue of apatient is performed manually.
 21. The method of effecting a change inthe surgical procedure of claim 17 wherein the step of contacting the pHelectrode to the tissue of a patient is performed by a percutaneouscatheter.
 22. The method of effecting a change in the surgical procedureof claim 17 wherein the step of contacting the pH electrode to thetissue of a patient is performed using one of a laparoscope, anendoscope and a colonscope.
 23. The method of effecting a change in thesurgical procedure of claim 17 wherein the tissue is myocardial tissue.24. A method of determining a change in a surgical procedure comprisingthe steps of: contacting tissue of a patient with a pH electrode;measuring the pH of the tissue with the pH electrode to monitor the pHof the tissue during the surgical procedure; determining if the tissuepH falls below a threshold level indicative of acidosis; and delayingweaning from cardiopulmonary bypass if the tissue pH measurement fallsbelow the threshold level indicative of acidosis.
 25. The method ofeffecting a change in the surgical procedure of claim 24 wherein thestep of contacting tissue further comprises inserting the pH electrodeinto the tissue.
 26. The method of effecting a change in the surgicalprocedure of claim 24 wherein the step of contacting the pH electrode tothe tissue of a patient is performed manually.
 27. The method ofeffecting a change in the surgical procedure of claim 24 wherein thestep of contacting the pH electrode to the tissue of a patient isperformed by a percutaneous catheter.
 28. The method of effecting achange in the surgical procedure of claim 24 wherein the step ofcontacting the pH electrode to the tissue of a patient is performedusing one of a laparoscope, an endoscope and a colonscope.
 29. Themethod of effecting a change in the surgical procedure of claim 24wherein the tissue is myocardial tissue.
 30. A method of controlling afluid delivery system based on pH data comprising the steps of:providing tissue pH data; determining if selected tissue pH data fallsbelow a threshold level indicative of a tissue condition; andcontrolling fluid flow in response to the determination.
 31. The methodof claim 30 further comprising the step of providing a controllerconnected to the delivery system.
 32. The method of claim 30 wherein thestep of controlling delivery of preservation fluid to a site furthercomprises the step of altering the flow rate of the fluid.
 33. Themethod of claim 30 wherein the step of controlling flow furthercomprises the step of altering a temperature of a preservation fluid.34. The method of claim 30 wherein the step of controlling flow furthercomprises the step of altering the site of delivery of the fluid. 35.The method of claim 30 wherein the step of controlling flow furthercomprises the step of directing the solution through a valve.
 36. Themethod of claim 30 wherein the method further comprises the step ofdisplaying changes in a procedure.
 37. The method of claim 30 furthercomprising providing temperature and fluid pressure data.
 38. The methodfor dispersing cardioplegia within a specific myocardial segmentcomprising: applying occlusive pressure to a coronary artery proximal tothe sight of insertion of a new vein graft; and perfusing a cardioplegicsolution through a proximal end of the graft.
 39. A method forpreventing cell apoptosis comprising: providing a pH electrode andmonitor; inserting the pH electrode into a tissue site; measuring tissuepH; and reversing tissue ischemia to prevent cell apoptosis.